Therapeutic azo-compounds for drug delivery

ABSTRACT

Polyazo compounds, which include low molecular weight drugs having a carboxylic acid group and an amine, thiol, alcohol or phenol group within their structure, formed into polymeric drug delivery systems are provided. Also provided are methods of producing polymeric drug delivery systems having these polyazo compounds as well as methods of administering low molecular weight drugs to a host via the polymeric drug delivery systems.

PRIORITY OF INVENTION

[0001] This application claims priority from U.S. Provisional PatentApplication No. 60/220,998, filed Jul. 27, 2000), which is incorporatedherein by reference.

BACKGROUND OF THE INVENTION

[0002] 5-Aminosalicylic acid (5-ASA) is the active component of acommonly used treatment for inflammatory bowel disease (IBD) and Crohn'sdisease treatment. 5-ASA drug is typically linked via an azo bond to acarrier that allows for targeted drug release exclusively in the largeintestine where the azo bond is cleaved by the indigenous bacteria.However, the carrier molecule for this component is associated withseveral side effects such as nausea and vomiting, rash, or other severetoxic reactions.

[0003] 4-Aminosalicylic acid (4-ASA) has shown promise in the treatmentof inflammatory bowel disease as well as tuberculosis. However, thisdrug causes several objectionable side effects. Some of the less commonside effects are hepatitis, hypokalemia, acute renal failure, mildhypoprothrombinemia, hemolytic anaemia and thrombocytopenia Patients canalso develop hypersensitivity and hypothyroidism and goiter. The sideeffects that makes this drug intolerable to patients, however, are thegastrointestinal reactions. 4-ASA is a gastrointestinal irritant whichfrequently causes symptoms of anorexia, nausea, vomiting, and diarrhea.The diarrhea can be severe enough to cause steatorrhea, malabsorption,secondary folic acid deficiency and megaloblastic anemia.

[0004] Accordingly, attempts have been made to prepare formulationswhich alleviate these side effects. Several formulations have beencreated which include enteric-coated tablets and granules, solutions,and suspensions, as well as chemically modified forms such as complexeswith resin and ascorbic acid, phenyl esters, and benzoyl amides. Severalpolymeric drugs incorporating 4-ASA based on either dialdehydestarch/oxidized cellulose, poly(vinyl alcohol), or polyacrylatebackbones have also been prepared.

[0005] In the present invention, drugs are incorporated into polymericsystems to furnish a polyazo compound. Using these polymeric drugdelivery systems, targeted and temporal drug delivery can be achieved,without unwanted side effects of the current formulations.

SUMMARY OF THE INVENTION

[0006] Polymeric polyazo compounds which degrade into usefulbiologically active compounds have now been developed. Accordingly, theinvention provides a polymer of the invention which comprises abackbone, wherein the backbone has an azo linkage, and. wherein thebackbone has one or more groups that will yield a biologically activecompound upon hydrolysis and cleavage of the azo-bond of the polymer.

[0007] The invention also provides a pharmaceutical compositioncomprising a polymer of the invention and a pharmaceutically acceptablecarrier.

[0008] The invention also provides a therapeutic method for treating adisease in an animal comprising administering to an animal in need ofsuch therapy, an effective amount of a polymer of the invention.

[0009] The invention also provides a method of delivering a biologicallyactive compound to a host comprising administering to the host abiocompatible and biodegradable polymer of the invention, which degradesinto the biologically active compound.

[0010] The invention provides a polymer of the invention for use inmedical therapy, as well as the use of a polymer of the invention forthe manufacture of a medicament useful for the treatment of a disease ina mammal, such as a human.

[0011] The invention also provides a therapeutic method for treatinginflammatory bowel disease, cancer, or a brain tumor comprisingadministering to a mammal in need of such therapy, an effective amountof a polymer of any one of formula (III), (IV) or (V), as describedherein.

[0012] The invention also provides a therapeutic method for producing ananti-infective effect in an animal comprising administering to an animalin need of such therapy, an effective amount of a polymer of any one offormula (III), (IV) or (V), as described herein.

[0013] The invention also provides a therapeutic method for treatingcancer comprising administering to an animal in need of such therapy, aneffective amount of a polymer of any one of formula (III), (IV) or (V),as described herein.

[0014] The invention also provides processes and intermediates disclosedherein that are useful for preparing a polymer of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0015] Definitions

[0016] The following definitions are used, unless otherwise described:halo is fluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc. denote bothstraight and branched groups; but reference to an individual radicalsuch as “propyl” embraces only the straight chain radical, a branchedchain isomer such as “isopropyl” being specifically referred to. Aryldenotes a phenyl radical or an ortho-fused bicyclic carbocyclic radicalhaving about nine to ten ring atoms in which at least one ring isaromatic. Heteroaryl encompasses a radical attached via a ring carbon ofa monocyclic aromatic ring containing five or six ring atoms consistingof carbon and one to four heteroatoms each selected from the groupconsisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absentor is H, O, (C₁-C₆)alkyl, phenyl or benzyl, as well as a radical of anortho-fused bicyclic heterocycle of about eight to ten ring atomsderived therefrom, particularly a benz-derivative or one derived byfusing a propylene, trimethylene, or tetramethylene diradical thereto.

[0017] The term anhydride linkage means —C(═O)—O—(O═)C—, term esterlinkage means —OC(═O) or —C(═O)O—; the term thioester linkage means—SC(═O)— or —C(═O)S—; and the term amide linkage means —N(R)C(═O)— or—C(═O)N(R)—, wherein each R is a suitable organic radical, such as, forexample, hydrogen, (C₁-C₆s)alkyl, (C₃-C₆)cycloalkyl(C₃-C₆)alkyl, aryl,heteroaryl, aryl(C₁-C₆)alkyl, or heteroaryl(C₁-C₆)alkyl.

[0018] The term “amino acid,” comprises the residues of the naturalamino acids (e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Ile, Leu,Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D or L form, as wellas unnatural amino acids (e.g. phosphoserine, phosphothreonine,phosphotyrosine, hydroxyproline, gamma-carboxyglutamate; hippuric acid,octahydroindole-2-carboxylic acid, statine,1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,ornithine, citruline, α-methyl-alanine, para-benzoylphenylalanine,phenylglycine, propargylglycine, sarcosine, and tert-butylglycine). Theterm also compnses natural and unnatural amino acids bearing aconventional amino protecting group (e.g. acetyl or benzyloxycarbonyl),as well as natural and unnatural amino acids protected at the carboxyterminus (e.g. as a (C₁-C₆)alkyl, phenyl or benzyl ester or amide; or asan α-methylbenzyl amide). Other suitable amino and carboxy protectinggroups are known to those skilled in the art (See for example, Greene,T. W., Wutz, P. G. M. “Protecting Groups In Organic Synthesis” secondedition, 1991, New York, John Wiley & sons, Inc., and references citedtherein).

[0019] The term “host” includes animnals and plants.

[0020] The term “peptide” describes a sequence of 2 to 35 amino acids(e.g. as defined hereinabove) or peptidyl residues. The sequence may belinear or cyclic. For example, a cyclic peptide can be prepared or mayresult from the formation of disulfide bridges between two cysteineresidues in a sequence. Preferably a peptide comprises 3 to 20, or 5 to15 amino acids. Peptide derivatives can be prepared as disclosed in U.S.Pat. Nos. 4,612,302; 4,853,371; and 4,684,620, or as described in theExamples hereinbelow. Peptide sequences specifically recited herein arewritten with the amino terminus on the left and the carboxy terminus onthe right.

[0021] Pohmers of the Invention

[0022] The biocompatible, biodegradable polyazo compounds of theinvention are useful in a variety of applications where delivery of abiologically active compound (active agent) to the large intestine isdesired.

[0023] The polymers of the invention may be prepared in accordance withmethods commonly employed in the field of synthetic polymers to producea variety of useful products with valuable physical and chemicalproperties. The polymers can be readily processed into tablets,coatings, and microspheres for delivery of the active agent.

[0024] Polymers of the present invention can also be incorporated intooral or rectal formulations.

[0025] Although the invention provides homopolymers that are preparedfrom suitably functionalized biologically active compounds, Applicanthas discovered that the mechanical and hydrolytic properties of polymerscomprising one or more biologically active compounds can be controlledby incorporating a linking group (L) into the polymer backbone.

[0026] Preferably, the polymers of the invention comprise backboneswherein biologically active compounds and linker groups are bondedtogether through anhydride linkages, ester linkages, thioester linkages,amide linkages, or a mixture thereof. Due to the presence of the linkinggroups, the polymers can be hydrolyzed under physiological conditions toprovide the azo-compounds containing the active agent Thus, the polymersof the invention can be particularly useful as a controlled releasesource for a biologically active compound, or as a medium for thelocalized delivery of a biologically active compound, to the lowerintestine. For example, the polymers of the invention can be used forthe localized delivery of a theraputic agent for treatment of intestinalconditions such as inflammatory bowel disease and Crohn's disease or forthe treatment of tuberculosis in a patient which comprises orallyadministering to the patient a polymeric drug delivery system comprisinga poly(azo-anhydride) of 5-ASA or 4-ASA.

[0027] Azo-polymers prepared in accordance with the present inventionhave average molecular weights of about 1500 daltons up to about 100,000daltons, calculated by Gel Permeation Chromatography (GPC) relative tonarrow molecular weight polystyrene standards. Preferred aromaticpolyanhydrides have average molecular weights of about 1500 daltons, upto about 50,000 daltons calculated by Gel Permeation Chromatography(GPC) relative to narrow molecular weight polystyrene standards.Preferred azo-polymers have average molecular weights of about 1500Daltons, up to about 35,000 Daltons.

[0028] In the chemically linked azo active agents of the polymeric drugdelivery system, drug release becomes dependant upon pH as well asbacterial degradation. For example, using the polyazo compounds of theinvention, a polymeric form of a current Crohn's disease drug,olsalazine, can be prepared which will undergo hydrolysis and bacterialdegradation (azo cleavage) to release the drug. In this embodiment, theonly active degradation product is the free drug, 5-ASA. Thus, sideeffects associated with current 5-ASA preparations are eliminated. Inaddition, the majority, if not all, of the drug is released at thetarget (large intestine) due to pH and indigenous flora. Further,polyanhydride linkages have been associated with intestinal mucosaladhesion, which may impart a beneficial temporal control aspect to thesematerials as well.

[0029] Another example is 4-ASA. 4ASA is associated with a lowbiological half-life, thus daily dosages can be on the order of ten tofifteen grams per day. By incorporating 4-ASA into a polymeric azocompound, specifically a poly(azo-anhydride) compound, the drug can bereleased gradually through cleavage of the azo bond by intestinalbacteria as it passes through the alimentary canal. In this way, it isexpected that 4-ASA will gradually be absorbed into the bloodstream.Thus, 4ASA serum levels can be maintained and stabilized over time. Thiscould eliminate the need for repeated doses. 4-ASA is also beinginvestigated as a treatment for inflammatory bowel disease in additionto its use as a tuberculostatic drug. Thus, polymeric drug deliverysystems comprising 4-ASA may have uses that parallel those of the 5-ASApolymers described above.

[0030] Biologically Active Compounds

[0031] The term “biologically active compound” includes therapeuticagents that provide a therapeutically desirable effect when administeredto an animal (eg., a mammal, such as a human). Biologically activecompounds that can be incorporated into the polymers of the inventionpossess at least two functional groups. One group can form the azo groupand the other that can each be incorporated into an anhydride, ester,thioester, or amide linkage of a polymer (as discussed in detail below),such that, upon hydrolysis of the polymer, the therapeutic agent isobtained. These groups can independently be a hydroxy group (—OH), amercapto group (—SH), an amine group (—NHR), or a carboxylic acid(—COOH).

[0032] The biologically active compounds can also comprise otherfunctional groups (including hydroxy groups, mercapto groups, aminegroups, and caxboxylic acids, as well as others) that can be used tomodify the properties of the polymer (e.g. for branching, for crosslinking, for appending other molecules (e.g. another biologically activecompound) to the polymer, for changing the solubility of the polymer, orfor effecting the biodistribution of the polymer). Lists of therapeuticagents can be found, for example, in: Physicians' Desk Reference, 55ed., 2001, Medical Economics Company, Inc., Montvale, N.J.; USPNDictionary of USAN and International Drug Names, 2000, The United StatesPharmacopeial Convention, Inc., Rockville, Md.; and The Merck Index, 12ed., 1996, Merck & Co., Inc., Whitehouse Station, N.J. One slilled inthe art can readily select therapeutic agents that possess the necessaryfunctional groups for incorporation into the polymers of the inventionfrom these lists.

[0033] Therapeutic agents that can be incorporated into the polymers ofthe invention include suitably functionalized analgesics, anesthetics,anti-convulsants, antidiabetic agents, anti-fibrotic agents,anti-infectives, anti-bacterials, anti-fungals, anti-thrombotics,anti-neoplastics, cardioprotective agents, cardiovascular agents,central nervous system stimulants, cholinesterase inhibitors,contraceptives, dopamine receptor agonists, erectile dysfunction agents,fertility agents, gastrointestinal agents, gout agents, hormones,immunomodulators, immunosuppressives, migraine agents, motion sicknessagents, muscle relaxants, non-steriodal anti-inflammatory drugs,nucleoside analogs, obesity agents, ophthalmic agents, osteoporosisagents, parasympatholytics, parasympathommetics, prostaglandins,psychotherapeutic agents, respiratory agents, sedatives, hypnotics,smoking cessation agents, sympatholytics, urinary tract agents, andvasodilators (see Physician's Desk Reference, 55 ed., 2001, MedicalEconomics Company, Inc., Montvale, N.J., pages 201-202).

[0034] Examples of anti-bacterial compounds suitable for use in thepresent invention include, but are not limited to2-p-sulfanilyanilinoethanol, 4,4′-sulfinyldianiline,4-sulfanilamidosalicylic acid, acediasulfone, acetosulfone, amikacin,amoxicillin, amphotericin B, ampicillin, apramycin, arbekacin,aspoxicillin, aztreonam, brodiroprim, butirosin, capreomycin, carumonam,cefadroxil, cefatrizine, cefclidin, cefdinir, cefditoren, cefepime,cefetamet, cefinenoxime, cefiniox, cefodizime, ceforanide, cefotaxime,cefotiam, cefozopran, cefpirome, cefprozil, cefroxadine, ceftazidime,cefteram, ceffibuten, ceftriaxone, cefuzonam, cephalexin, cephaloglycin,cephalosporin C, cephradine, clinafloxacin, colistin, cyclacillin,dapsone, diathymosulfone, dibekacinm, enviomycinm, epicillin,forimicin(s), gentamicin(s), gramicidin S, iseparicin, kanamycin(s),lucensomycin, lymecycline, micronomicin, natamycin, neomycin,netilmicin, paromomycin, pazumfloxacin, penicillin N, peplomycin,perimycin A, polymyxin, p-sulfanilylbenzylamine, ribostamycin,ristocetin, sisomicin, sparfloxacin, succisulfone, suluicirysoidine,sulfamidochrysoidine, sulfanilic acid, sulfoxone, teicoplanin,tetroxoprim, thiazolsulfone, tigemonam, tobramycin, tosufloxacin,trimethoprim, trovafloxacin, tuberactinomycin, vancomycin and the like.

[0035] Examples of anti-fungal compounds suitable for use in the presentinvention include, but are not limited to azaserine, candicidin(s),mepartricin, nystatin, tubercidin and the like.

[0036] Examples of anti-neoplastic compounds suitable for use in thepresent invention include, but are not limited to6diazo-5-oxo-L-norleucine, azacitadine, azaserine, bleomycin(s),carubicin, cladnibine, cytarabine, daunorubicin, denopterin,doxorubicin, edatrexate, eflornithine, epirubicin, fludarabine,gemcitabine, idarubicin, melphalan, methotrexate, mitomycin C,pirarubicin, piritrexim, pteropterin, puromycin, streptoigrin,thiamiprine, thioguanine, trimetrexate, tubercidin, ubenimex, zorubicinand the like.

[0037] Examples of immunosuppressive compounds suitable for use in thepresent invention include, but are not limited to gusperimus, ubenimexand the like.

[0038] Examples of local anesthetic compounds suitable for use in thepresent invention include, but are not limited to butethamine, naepaine,orthocaine, piridocaine and the like.

[0039] Examples of NSAID compounds suitable for use in the presentinvention include, but are not limited to 3-amino-4-hydroxybutyric acid,amfenac, bromfenac, mesalamine, S-adenosylmethionine and the like.

[0040] Linking Group “L”

[0041] The nature of the linking group “L” in a polymer of the inventionis not critical provided the polymer of the invention possessesacceptable mechanical properties and release linetics for the selectedtherapeutic application. The linking group L is typically a divalentorganic radical having a molecular weight of from about 25 daltons toabout 400 daltons. More preferably, L has a molecular weight of fromabout 40 daltons to about 200 daltons.

[0042] The lining group L typically has a length of from about 5angstroms to about 100 angstroms using standard bond lengths and angles.More preferably, the linking group L has a length of from about 10angstroms to about 50 angstroms.

[0043] The linking group may be biologically inactive, or may itselfpossess biological activity. The linking group can also comprise otherfunctional groups (including hydroxy groups, mercapto groups, aminegroups, carboxylic acids, as well as others) that can be used to modifythe properties of the polymer (e.g. for branching, for cross linking,for appending other molecules (e.g. another biologically activecompound) to the polymer, for changing the solubility of the polymer, orfor effecting the biodistribution of the polymer).

[0044] Specific and Preferred Values

[0045] Specific and preferred values listed herein for radicals,substituents, groups, and ranges, are for illustration only; they do notexclude other defined values or other values within defined ranges forthe radicals and substituents.

[0046] Specifically, (C₁-C₆)alkyl can be methyl, ethyl, propyl,isopropyl, butyl iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl;(C₃-C₆)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl; (C₃-C₆)cycloalkyl(C₁-C₆)alkyl can be cyclopropylmethyl,cyclobutyhnethyl, cyclopentylmethyl, cyclohexylmethyl,2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, or2-cyclohexylethyl; (C₁-C₆)alkoxy can be methoxy, ethoxy, propoxy,isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, orhexyloxy; (C₁-C₆)alkanoyl can be acetyl propanoyl or butanoyl;(C₁-C₆)alkoxycarbonyl can be methoxycaxbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, orhexyloxycarbonyl; (C₁-C₆)alkylthio can be methylthio, ethylthio,propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, orhexylthio; (C₂-C₆)alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy,isobutanoyloxy, pentanoyloxy, or hexanoyloxy; aryl can be phenyl,indenyl, or naphthyl; and heteroaryl can be furyl, imidazolyl,triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl,pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide),thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or itsN-oxide) or quinolyl (or its N-oxide).

[0047] A specific biologically active compound that can be incorporatedinto the polymers of the invention is 5-aminosalicylic acid,4aaminosalicylic acid, 2-p-sulfanilyanilinoethanol,4,4′-sulfinyldianiline, 4sulfanilamidosalicylic acid, acediasulfone,acetosulfone, amikacin, amoxicillin, amphotericin B, ampicillin,apramycin, arbekacin, aspoxicillin, aztreonam, brodimoprim, butirosin,capreomycin, carumonam, cefadroxil, cefatrizine, cefclidin, cefdinir,cefditoren, cefepime, cefetamet, cefixime, cefmenoxime, cefminox,cefodizime, ceforanide, cefotaxime, cefotiam, cefozopran, cefpirome,cefprozil, cefroxadine, ceftazidime, cefteram, ceftibuten, ceftriaxone,cefuzonam, cephalexin, cephaloglycin, cephalosporin C, cephradine,clinafloxacin, colistin, cyclacillin, dapsone, diathymosulfone,dibekacinm, enviomycinm, epicillin, fortimicin(s), gentamicin(s),gramicidin S, isepamicin, kanamycin(s), lucensomycin, lymecycline,micronomicin, natamycin, neomycin, netilmicin, paromomycin,pazufloxacin, penicillin N, peplomycin, perimycin A, polymyin,p-sulfanilylbenylamine, ribostamycin, ristocetin, sisomicin,sparfloxacin, succisulfone, sulfacbrysoidine, sulfamidochrysoidine,sulfanilic acid, sulfoxone, teicoplanin, tetroxoprin, thiazolsulfone,tigemonam, tobramycin, tosufloxacin, trimethoprim, trovafloxacin,tuberactinomycin, vancomycin, azaserine, candicidin(s), meparicin,nystatin, tubercidin, 6-diazo5-oxo-L-norleucine, azacitadine, azaserine,bleomycin(s), carubicin, cladribine, cytarabine, daunorubicin,denopterin, doxorubicin, edatrexate, eflornithine, epirubicin,fludarabine, gemcitabine, idarubicin, melphalan, methotrexate, mitomycinC, pirarubicin, piritrexim, pteropterin, puromycin, sreptonigrin,thiamiprine, thioguanine, trimetrexate, tabercidin, ubenimex, zorubicin,gusperimus, butetharnine, naepaine, orthocaine, piridocaine,3-amino4-hydroxybutyric acid, amfenac, bromfenac, mesalamine, orS-adenosylmethionine.

[0048] A preferred biologically active compound suitable forincorporation into polymeric polyazo compounds of the invention is5-aminosalicylic acid or 4aminosalicylic acid.

[0049] Another specific value for L is a divalent, branched orunbranched, saturated or unsaturated, hydrocarbon chain, having from 1to 25 carbon atoms, wherein the chain is optionally substituted oncarbon with one or more (e.g. 1, 2, 3, or 4) substituents selected fromthe group consisting of (C₁-C₆)alkoxy, (C₃-C₆)cycloaikyl,(C₁-C₆)alkanoyl, (C₁-C₆)alkoyloxy, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy,aryl, aryloxy, heteroaryl, and heteroaryloxy.

[0050] Another specific value for L is an amino acid.

[0051] Another specific value for L is a peptide Another specific valuefor L is a divalent, branched or unbranched, saturated or unsaturated,hydrocarbon chain, having from 1 to 25 carbon atoms, wherein one or more(e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced by (—O—)or (—NR—).

[0052] A more specific value for L is a divalent, branched orunbranched, saturated or unsaturated, hydrocarbon chain, having from 3to 15 carbon atoms, wherein one or more (e.g. 1, 2, 3, or 4) of thecarbon atoms is optionally replaced by (—O —) or (—NR—), and wherein thechain is optionally substituted on carbon with one or more (e.g. 1, 2,3, or 4) substituents selected from the group consisting of(C₁-C₆)alkoxy, (C₃-C₆)cycloallkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alknoyloxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylthio, azido, cyano, nitro, halo,hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy.

[0053] Another more specific value for L is a divalent, branched orunbranched, saturated or unsaturated, hydrocarbon chain, having from 3to 15 carbon atoms, wherein one or more (e.g. 1, 2, 3, or 4) of thecarbon atoms is optionally replaced by (—O—) or (—NR—).

[0054] Another more specific value for L is a divalent, branched orunbranched, saturated or unsaturated, hydrocarbon chain, having from 3to 15 carbon atoms.

[0055] Another more specific value for L is a divalent, branched orunbranched, hydrocarbon chain, having from 3 to 15 carbon atoms.

[0056] A preferred value for L is a divalent, branched or unbranched,hydrocarbon chain, having from 6 to 10 carbon atoms.

[0057] A more preferred value for L is a divalent hydrocarbon chainhaving 7, 8, or 9 carbon atoms.

[0058] A most preferred value for L is a divalent hydrocarbon chainhaving 8 carbon atoms.

[0059] A specific polymer of the invention comprises one or more monomerunits of formula (I):

-A-R¹-N═N-R¹(A-L)_(n)-  (I)

[0060] and will have formula (II)

(A-R¹-N═N-R¹-(A-L)_(n))_(x)-  (II)

[0061] wherein each R¹-N is a group that will provide a biologicallyactive compound upon hydrolysis of the polymer, each A is an anhydride,an amide linkage, a thioester linkage, or an ester linkage; and L is alinking group; where n is 0 or 1 and x represents the number ofrepeating groups (e.g. x can be an integer from 2 to about 100,preferably from 2 to about 50, and more preferably, from 5 to 50).Suitable monomers are polymerized to provide the polyazo compounds.

[0062] Such a polymer, wherein each R¹ is a group that will provide adifferent biologically active compound upon hydrolysis of the polymer,are particularly useful for the administration of a combination of twotherapeutic agents to an animal.

[0063] A preferred group of polyazo compounds includes compoundscontaining at least one free amine group to form the azo group and atleast one free carboxylic acid group, alcohol group or amine groupavailable for reactions which can self-polymerize or copolymerize withcarboxylic acid groups or bis(acyl) chlorides.

[0064] A specific polymeric drug delivery system for oral delivery of adrug comprises a drug incorporated in a poly(azo-anhydride).

[0065] A specific polymeric drug delivery system for oral delivery of adrug comprises a poly(azo-anhydride) where the drug is 5-ASA or 4-ASA.

[0066] A specific method of the invention is orally delivering a drug toa patient by administering to the patient the polymeric drug deliverysystem of a drug incorporated in a poly(azo-anhydride).

[0067] A specific method of the invention is treating intestinalconditions in a patient comprising orally administering to the patientthe polymeric drug delivery system where the drug is 5-ASA or 4-ASA.

[0068] Another specific method of the invention is treating tuberculosisin a patient comprising orally administering to the patient a polymericdrug delivery system of the invention wherein the drug is 4-ASA.

[0069] Another specific method of the invention is producing oralformulations of a drug which provide for targeted drug release andcontrolled systemic absorption comprising incorporating a drug into apoly(azo-anhydride) compound.

[0070] Formulations

[0071] The polymers of the invention can be formulated as pharmaceuticalcompositions and administered to a mammalian host, such as a humanpatient in a variety of forms adapted to the chosen route ofadministration, i.e., orally or rectally. For some routes ofadministration, the polymer can conveniently be formulated as micronizedparticles.

[0072] Thus, the present compounds may be systemically administered,e.g., orally, in combination with a pharmaceutically acceptable vehiclesuch as an inert diluent or an assimilable edible carrier. They may beenclosed in hard or soft shell gelatin capsules, may be compressed intotablets, or may be incorporated directly with the food of the patient'sdiet. For oral therapeutic administration, the active compound may becombined with one or more excipients and used in the form of ingestibletablets, buccal tablets, troches, capsules, elixirs, suspensions,syrups, wafers, and the like. Such compositions and preparationspreferably contain at least 0.1% of polymer by weight. The percentage ofthe compositions and preparations may, of course, be varied and mayconveniently be between about 2 to about 60% of the weight of a givenunit dosage form. The amount of polymer in such therapeutically usefulcompositions is such that an effective dosage level will be obtained.

[0073] The tablets, troches, pills, capsules, and the like may alsocontain the following: binders such as gum tragacanth, acacia, cornstarch or gelatin; excipients such as dicalcium phosphate; adisintegrating agent such as corn starch, potato starch, alginic acidand the like; a lubricant such as magnesium stearate; and a sweeteningagent such as sucrose, fructose, lactose or aspartame or a flavoringagent such as peppermint, oil of wintergreen, or cherry flavoring may beadded. When the unit dosage form is a capsule, it may contain, inaddition to materials of the above type, a liquid carrier, such as avegetable oil or a polyethylene glycol. Various other materials may bepresent as coatings or to otherwise modify the physical form of thesolid unit dosage form. For instance, tablets, pills, or capsules may becoated with gelatin, wax, shellac or sugar and the like. A syrup orelixir may contain the active compound, sucrose or fuctose as asweetening agent, methyl and propylparabens as preservatives, a dye andflavoring such as cherry or orange flavor. Of course, any material usedin preparing any unit dosage form should be pharmaceutically acceptableand substantially non-toxic in the amounts employed. In addition, theactive compound may be incorporated into sustained-release preparationsand devices.

[0074] Useful solid carriers include finely divided solids such as talc,clay, microcrystalline cellulose, silica, alumina and the like. Usefulliquid carriers include alcohols or glycols or alcohol/glycol blends, inwhich the present compounds can be dissolved or dispersed at effectivelevels, optionally with the aid of non-toxic surfactants. Adjuvants suchas fragrances and additional antimicrobial agents can be added tooptimize the properties for a given use.

[0075] Dosages

[0076] Useful dosages of the polymers can be determined by comparingtheir in vitro activity, and in vivo activity of the therapeutic agentin animal models. Methods for the extrapolation of effective dosages inmice, and other animals, to humans are known to the art; for example,see U.S. Pat. No. 4,938,949. Additionally, useful dosages can bedetermined by measuring the rate of hydrolysis for a given polymer undervarious physiological conditions. The amount of a polymer required foruse in treatment will vary not only with the particular polymer selectedbut also with the route of administration, the nature of the conditionbeing treated and the age and condition of the patient and will beultimately at the discretion of the attendant physician or clinician.

[0077] The desired dose may conveniently be presented in a single doseor as divided doses administered at appropriate intervals, for example,as two, three, four or more sub-doses per day. The sub-dose itself maybe further divided, e.g., into a number of discrete loosely spacedadministrations.

[0078] The present invention also relates to methods of usingcompositions comprising drugs incorporated into polyazo compounds in anyapplication wherein oral delivery of the drug is desired. The quantityof drug in the polyazo compound to be administered to a patient which iseffective for the selected use can be readily determined by those ofordinary skill in the art without undue experimentation. The quantityessentially corresponds stoichiometrically to the amount of drug whichis known to produce an effective treatment for the selected use.

[0079] Combination Therapies

[0080] The polymers of the invention are also useful for administering acombination of therapeutic agents to an animal. Such a combinationtherapy can be carried out in the following ways: 1) a secondtherapeutic agent can be dispersed within the polymer matrix of apolymer of the invention, and can be released upon degradation of thepolymer; 2) a second therapeutic agent can be appended to a polymer ofthe invention (i.e. not in the backbone of the polymer) with bonds thathydrolyze to release the second therapeutic agent under physiologicalconditions; 3) the polymer of the invention can incorporate twotherapeutic agents into the polymer backbone (e.g. a polymer comprisingone or more units of formula (I)) or 4) two polymers of the invention,each with a different therapeutic agent can be administered together (orwithin a short period of time).

[0081] Thus, the invention also provides a pharmaceutical compositioncomprising a polymer of the invention and a second therapeutic agentthat is dispersed within the polymer matrix of a polymer of theinvention. The invention also provides a pharmaceutical compositioncomprising a polymer of the invention having a second therapeutic agentappended to the polymer (e.g. with bonds that will hydrolyze to releasethe second therapeutic agent under physiological conditions).

[0082] The polymers of the invention can also be administered incombination with other therapeutic agents that are effective to treat agiven condition to provide a combination therapy. Thus, the inventionalso provides a method for treating a disease in a mammal comprisingadministering an effective amount of a combination of a polymer of theinvention and another therapeutic agent The invention also provides apharmaceutical composition comprising a polymer of the invention,another therapeutic agent, and a pharmaceutically acceptable carrier.

[0083] Preparation Of Polymers Of The Invention

[0084] Processes for preparing polymers of the invention are provided asfurther embodiments of the invention and are illustrated by thefollowing procedures in which the meanings of the generic radicals areas given above unless otherwise qualified.

[0085] In general, the polymers of the invention can be prepared, asillustrated in Scheme 1, from an azo containing compound, which canrelease a biologically active compound, of formula (X₁-R¹-N═N-R¹-X₂) anda linker precursor of formula Z₁-L-Z₂, wherein X₁, X₂, Z₁, and Z₂ areindependently selected from the values in the table below.

[0086] wherein n is 0 or 1; and x represents the number of repeatingunits.

[0087] The azo containing compound and the linker precursor can bepolymerized using well known synthetic techniques (e.g. by condensation)to provide a polymer of the invention (I) wherein each R¹ is a groupthat will provide a biologically active compound upon hydrolysis of thepolymer and cleavage of the azo-bond; each A is an anhydride linkage, anamide linkage, a thioester linkage, or an ester linkage; L is a linkinggroup and n is 0 or 1.

[0088] Depending on the reactive functional group (X₁ or X₂) of thebiologically active compound, a corresponding functional group (Z₁ orZ₂) can be selected from the following table, to provide an anhydridelinkage, ester linkage, thioester linkage, or amide linkage in thepolymer backbone. Functional Group On Biologically active FunctionalGroup On compound Linker Precursor Resulting Linkage In (X₁ or X₂) (Z₁or Z₂) Polymer —COOH —COOH Anhydride —COOH —OH Ester —COOH —NHR Amide—COOH —SH Thioester —OH —COOH Ester —SH —COOH Thioester —NHR —COOH Amide

[0089] As will be clear to one skllled in the art, suitable protectinggroups can be used during the reaction illustrated in Scheme 1 (and inthe reactions illustrated in Schemes 2-6 below). For example, otherfunctional groups present in the biologically active compound or thelinker precursor can be protected during polymerization, and theprotecting groups can subsequently be removed to provide the polymer ofthe invention. Suitable protecting groups and methods for theirincorporation and removal are well known in the art (see for exampleGreene, T. W.; Wutz, P. G. M. “Protecting Groups In Organic Synthesis”second edition, 1991, New York, John Wiley & sons, Inc.).

[0090] Additionally, when a carboxylic acid is reacted with a hydroxygroup, a mercapto group, or an amine group to provide an ester linkage,thioester linkage, or an amide linkage, the carboxylic acid can beactivated prior to the reaction, for example, by formation of thecorresponding acid chloride. Numerous methods for activating carboxylicacids, and for preparing ester linkages, thioester linkages, and amidelinkages, are known in the art (see for example Advanced OrganicChemistry: Reaction Mechanisms and Structure, 4 ed., Jerry March, JohnWiley & Sons, pages 419-437 and 1281).

[0091] A polyester of the invention can be formed from an azo containingcompound of formula (HO—R¹-N═N-R¹—OH) and from a linker precursor offormula HOOC-L-COOH as illustrated in Scheme 2.

[0092] wherein x represents the number of repeating units. Reaction ofthe hydroxy groups of the azo containing compound with the carboxylicacids of the linker precursor provides a polymer of formula (III), whichis a polymer of the invention.

[0093] A polyamide of the invention can be prepared using a proceduresimilar to that illustrated in Scheme 2 by replacing the biologicallyactive dihydroxy compound in Scheme 2 with a suitable biologicallyactive diamino compound.

[0094] A polythioester of the invention can be prepared using aprocedure similar to that illustrated in Scheme 2 by replacing thebiologically active dihydroxy compound in Scheme 2 with a suitable azodimercapto compound.

[0095] A polyester/polyamide of the invention can be formed from abiologically active compound of formula (H(R)N—R¹—N═N—R¹—OH) and from alinker precursor of formula HOOC-L-COOH as illustrated in Scheme 3.

[0096] wherein x represents the number of repeating units. Reaction ofthe hydroxy group and the amino group of the azo compound with thecarboxylic acids of the linker precursor provides a polymer of formula(IV), which is a polymer of the invention.

[0097] Similarly, a polyester of the invention can be formed from an azocontaining compound of formula (HO—R¹—N═N—ROOH) and from a linkerprecursor of formula HOOC-L-OH as illustrated in Scheme 4.

[0098] wherein x represents the number of repeating units. Reaction ofthe hydroxy groups with the carboxylic acid groups provides a polymer offormula (V), which is a polymer of the invention.

[0099] In Schemes I-IV, each R¹ is independently a group that winprovide a biologically active compound upon hydrolysis of the polymerand cleavage of the azo-bond; each A is an anhydride linkage, an amidelinkage, a thioester linkage, or an ester linkage; L is a linking group;n is 0 or 1; and x is 2 to about 100 (or 2 to about 50; or 5 to about50).

[0100] Other polymers of the invention can be formed using the reactionsdescribed herein, using staring materials that have suitable groups toprepare the desired polymer.

[0101] Polymeric drug delivery systems of the present invention can becharacterized by proton nuclear magnetic resonance (EMS) spectroscopy,bred (IR) spectroscopy, gel permeation chromatography (GPC), highperformance liquid chromatography (HPLC), differential scanningcalorimetry (DSC), and thermal gravimetric analysis (TGA). For infradspectroscopy, samples are prepared by solvent casting on NaCl plates. ¹Hand ¹³C NMR spectroscopy is obtained in solutions of CDCl₃ or DMSO-d₆with solvent as the internal reference.

[0102] GPC is performed to determine molecular weight andpolydispersity. In this method, samples are dissolved in tetrahydrofuranand eluted through a mixed bed column (PE PL gel, 5 μm mixed bed). at aflow rate of 0.5 mL/minute. It is preferred that the samples (about 5mg/mL) be dissolved into the tetrahydrofaran and filtered using 0.5 μmPTFE syringe filters prior to column injection. Molecular weights aredetermined relative to narrow molecular weight polystyrene standards(Polysciences, Inc.).

[0103] Thermal analysis can also be performed using a system such as thePerkin-Elmer system consisting of a TGA 7 thermal gravimetric analyzerequipped with PE AD-4 autobalance and Pyris 1 DSC analyzer. In thissystem, Pyris software is used to carry out data analysis on a DECVenturis 5100 computer. For DSC, an average sample weight of 5-10 mg isheated at 10° C./minute at a 30 psi flow of N₂. For TGA, an averagesample weight of 10 mg is heated at 20° C./minute under a 8 psi flow ofN₂. Sessile drop contact angle measurements are obtained with an NRLGoniometer (Rame-hart) using distilled water. Solutions of polymer inmethylene chloride (10% wt/volume) are spun-coated onto glass slips, at5,000 rpm for 30 seconds.

[0104] Degradation and drug release profiles of the polymer drugdelivery systems of the present invention can also be determinedroutinely. For these experiments, the polymers are processed into eitherfilms, pellets, microspheres, nanospheres or fibers (depending on theirproperties). After processing, the materials are be characterired todetermine if any physicochemincal changes have occurred duringprocessing. Uniform processed, weighed, and characteried samples arethen degraded in acidic, neutral, and basic phosphate buffer (conditionschosen to simulate physiological range) in triplicate. Periodically thebuffer is removed and replaced with fresh media to simulate sinkconditions. The spent buffer is analyzed by HPLC to determine thecumulative release of the drug. At defined time periods, samples areremoved from the buffer and superficially dried (blotted). They are thenweighed to determine the water uptake. At this point, the contact angle(hydrated) is also measured to determine changes in hydrophobicityduring degradation. The samples are then thoroughly dried under vacuumand weighed to determine their mass loss. Contact angles (dry) aremeasured again to determine the hydrophobicity of the dry material, andhow it compares to that of the hydrated material. By plotting cumulativerelease of the degradation products over time, the degradation kineticscan be defined. For the polyazo polymers the degradation productcontains an amino groups (the free drug is only obtained with enzymaticcleavage of the azo bond). Wet and dry polymer weights over timeindicate if the material is bulk or surface eroding. If there is anincrease in water uptake, it can be determined that the polymer is bulkeroding, whereas if there is little or no water uptake the material isconsidered surface-eroding. By plotting the changes in dry weight versustime, the mass lost by the polymer as it erodes can be determined. Thisinformation will give additional insight into how the material isdegrading. Changes in molecular weight over time are also examined tobolster the degradation results.

[0105] Polyazo compounds used in the present invention can be isolatedby known methods commonly employed in the field of synthetic polymers toproduce a variety of useful products with valuable physical and chemicalproperties. Polymeric drug delivery systems can be readily processedinto tablets, coatings, and microspheres, and may also be processed bycompression molding and extrusion. In a preferred embodiment, thepolyazo compounds of the present invention are incorporated into oralformulations such as tablets, capsules, or liquid suspensions.

EXAMPLE 1

[0106] The polymeric drug delivery systems of the present inventioncomprising 5-ASA incorporated into a polyazo compound can be preparedfollowing Scheme 5. In Scheme 5, 5-nitrosalicylic acid is dimerzed viaazo linkage to form olsalazine using sodium hydroxide and zinc dust inmethanol/water. Alternatively, the disodium salt of the diacid(olsalazine) can be purchased from Pharmacia-Upjohn. The azo compound isthen converted to the activated monomer (bis-anhydride) by heating it atreflux in acetic anhydride. The monomer is polymerized by heating undervacuum to provide the polyazo compound where x, the number of repeatingunits, is from 2 to about 10.

EXAMPLE 2

[0107] In Example 2, Scheme 6 illustrates the synthesis of apoly(azo-anhydride) compound linking 4-ASA. The 4-aminosalicylic acid isconverted to its methyl ester with sulfuric acid in methanol.Methyl-4-aminosalicylate is dimerized via azoxy linkage with hydrogenperoxide in acetic acid. The azoxy compound is reduced to the hydrazocompound with zinc dust in acetic acid. The hydrazo compound is oxidizedto the azo compound with sodium perforate in acetic acid. The methylesters are cleaved with alkali to give the prepolymer azo diacid. Thediacid is converted to the activated monomer by refluxing in an excessof acetic anhydride. The monomer is then converted to the polyazocompound.

[0108] Activity

[0109] The ability of a polymer of the invention to produce a giventherapeutic effect can be determined using in vitro and in vivopharmacological models which are well known to the art.

[0110] All publications, patents, and patent documents (including theentire contents of U.S. Provisional Patent Application No. 60/220,998 ,filed Jul. 27, 2000) are incorporated by reference herein, as thoughindividually incorporated by reference. The invention has been describedwith reference to various specific and preferred embodiments andtechniques. However, it should be understood that many variations andmodifications may be made while remaining within the spirit and scope ofthe invention.

What is claimed is:
 1. A polymer comprising a backbone, wherein thebackbone comprises one or more azo linkages, and wherein the backbonecomprises one or more groups that will yield a biologically activecompound upon hydrolysis of the polymer.
 2. The polymer of claim 1 whichcomprises one or more units of formula (I) in the backbone:-A-R¹-N═N—R¹-(A-L)_(n)-  (I) wherein each R¹-N is a group that willprovide a biologically active compound upon hydrolysis of the polymer;each A is independently an anhydride linkage, an amide linkage, athioester linkage, or an ester linkage; L is a linking group; and n is 0or
 1. 3. The polymer of claim 1 or 2 wherein the biologically activecompound is a non-steriodal anti-inflammatory drug, an anti-bacterialdrug, an anti-fungal drug, an anti-cancer drug, an anti-thrombotic drug,an immunosuppressive drug, an analgesic drug or an anesthetic drug. 4.The polymer of claims 1 or 2, wherein the biologically active compoundis 5-aminosalicylic acid, 4-aminosalicylic acid,2-p-sulfanilyanilinoethanol, 4,4′-sulfinyldianiline,4-sulfanilamidosalicylic acid, acediasulfone, acetosulfone, amikacin,amoxicillin, amphotericin B, ampicillin, apramycin, arbekacin,aspoxicillin, aztreonam, brodimoprim, butirosin, capreomycin, carumonam,cefadroxil, cefatrizine, cefclidin, cefdinir, cefditoren, cefepime,cefetarnet, cefixime, cefinenoxime, cefiniox, cefodizime, ceforanide,cefotaxime, cefotiam, cefozopran, cefpirome, cefprozil, cefroxadine,ceftazidime, cefteram, ceftibuten, ceftriaxone, cefizonam, cephalexin,cephaloglycin, cephalosporin C, cephrdine, clinafloxacin, colistin,cyclacillin, dapsone, diathymosulfone, dibekacinm, enviomycinm,epicillin, fortimicin(s), gentamicin(s), gramicidin S, isepamicin,kanamycin(s), lucensomycin, lymecycline, micronomicin, natamycin,neomycin, netilmicin, paromomycin, pazufloxacin, penicillin N,peplomycin, perimycin A, polymyin, p-sulfarilylbenzylamine,ribostamycin, ristocetin, sisomicin, sparfloxacin, succisulfone,sulfachrysoidine, sulfamidochrysoidine, sulfanilfc acid, sulfoxone,teicoplanin, tetroxoprim, thiazolsulfone, tigemonam, tobramycin,tosufloxacin, trimethoprim, trovafloxacin, tuberactiomycin, vancomycin,azaserine, candicidin(s), mepartricin, nystatin, tubercidin,6-diazo-5-oxo-L-norleucine, azacitadine, bleomycin(s), carubicin,cladribine, cytarabine, daunorubicin, denopterin, doxorubicin,edatrexate, eflornithine, epirubicin, fludarabine, gemcitabine,idarubicin, melphalan, methotrexate, mitomycin C, pirarubicin,piritrexim, pteropterin, puromycin, streptonigrin, thiamiprine,thioguanine, trimetrexate, tubercidin, zorubicin, gusperimus, ubenimex,butethamine, naepaine, orthocaine, piridocaine, 3-amino-4-hydroxybutyricacid, amfenac, bromfenac, mesalamine, or S-adenosylmethionine.
 5. Thepolymer of claim 4, wherein the biologically active compound is5-aminosalicylic acid or 4-aminosalicylic acid.
 6. The polymer of claim4, wherein the biologically active compound is2-p-sulfanilyanilinoethanol, 4,4′-sulfinyldianiline,4-sulfanilamidosalicylic acid, acediasulfone, acetosulfone, amikacin,amoxicillin, amphotericin B, ampicillin, apramycin, arbekacin,aspoxicillin, aztreonam, brodimoprim butirosin, capreomycin, carumonam,cefadroxil, cefatrizine, cefclidin, cefdinir, cefditoren, cefepime,cefetarnet, cefixime, cefmenoxime, cefminox, cefodizime, ceforanide,cefotaxime, cefotiam, cefozopran, cefpirome, cefprozil, cefroxadine,ceftazidime, cefteram, ceftibuten, ceftriaxone, cefuzonam, cephalexin,cephaloglycin, cephalosporin C, cephradine, clinafloxacin, colistin,cyclacillin, dapsone, diathymosulfone, dibekacinm, enviomycinm,epicillin, fortimicin(s), gentamicin(s), gramicidin S, isepamicin,kanamycin(s), lucensomycin, lymecycline, micronomicin, natamycin,neomycin, netilmicin, paromomycin, pazufloxacin, penicillin N,peplomycin, perimycin A, polymyxin, p-sulfanilylbenzylamine,ribostamycin, ristocetin, sisomicin, sparfloxacin, succisulfone,sulfachrysoidine, sulfamidochrysoidine, sulfanilic acid, sulfoxone,teicoplanin, tetroxoprim, thiazolsulfone, tigemonam, tobramycin,tosufloxacin, trimethoprim, trovafloxacin, tuberactinomycin orvancomycin.
 7. The polymer of claim 4, wherein the biologically activecompound is azaserine, candicidin(s), mepartrcin, nystalin, tubercidin.8. The polymer of claim 3, wherein the biologically active compound is anon-steriodal anti-inflammatory drug.
 9. The polymer of claim 8, whereinthe biologically active compound is 3-amino-4-hydroxybutyric acid,amfenac, bromfenac, mesalamine- or S-adenosylmethionine.
 10. The polymerof claim 4, wherein the biologically active compound is6-diazo-5-oxo-L-norleucine, azacitadine, azaserine or bleomycin,carubicin, cladribine, cytarabine, daunorubicin, denopterin,doxorubicin, edatrexate, eflornithine, epirubicin, fludarabine,gemcitabine, idarubicin, melphalan, methotrexate, mitomycin C,pirarubicin, piritrexim, pteropterin, puromycin, streptonigrin,thiamiprine, thioguanine, trimetrexate, tubercidin, ubenimex orzorubicin.
 11. The polymer of claim 4, wherein the biologically activecompound is gusperimus or ubenimex.
 12. The polymer of claim 4, whereinthe biologically active compound is butethamine, naepaine, orthocaine orpiridocaine.
 13. The polymer of claim 2, wherein L is a divalent,branched or unbranched, saturated or unsaturated, hydrocarbon chain,having from 1 to 25 carbon atoms, wherein one or more (e.g. 1, 2, 3, or4) of the carbon atoms is optionally replaced by (—O—) or (—NR—), andwherein the chain is optionally substituted on carbon with one or more(e.g. 1, 2, 3, or 4) substituents selected from the group consisting of(C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylthio, azido, cyano, nitro, halo,hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy. 14.The polymer of claim 13, wherein L is a divalent, branched orunbranched, saturated or unsaturated, hydrocarbon chain, having from 1to 25 carbon atoms, wherein the chain is optionally substituted oncarbon with one or more (e.g. 1, 2, 3, or 4) substituents selected fromthe group consisting of (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl,(C₁-C₆)alkanoyl, (C₁-C₆)alkoyloxy, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy,aryl, aryloxy, heteroaryl, and heteroaryloxy.
 15. The polymer of claim2, wherein L is a peptide.
 16. The polymer of claim 2, wherein L is anamino acid.
 17. The polymer of claim 2, wherein L is a divalent,branched or unbranched, saturated or unsaturated, hydrocarbon chain,having from 1 to 25 carbon atoms, wherein one or more (e.g. 1, 2, 3, or4) of the carbon atoms is optionally replaced by (—O—) or (—NR—). 18.The polymer of claim 2, wherein L is a divalent, branched or unbranched,saturated or unsaturated, hydrocarbon chain, having from 3 to 15 carbonatoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms isoptionally replaced by (—O—) or (—NR—), and wheren the chain isoptionally substituted on carbon with one or more (e.g. 1, 2, 3, or 4)substituents selected from the group consisting of (C₁-C₆)alkoxy,(C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylthio, azido, cyano, nitro, halo,hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy. 19.The polymer of claim 2, wherein L is a divalent, branched or unbranched,saturated or unsatarated, hydrocarbon chain, having from 3 to 15 carbonatoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms isoptionally replaced by (—O—) or (—NR—).
 20. The polymer of claim 2,wherein L is a divalent, branched or unbranched, saturated orunsaturated, hydrocarbon chain, having from 3 to 15 carbon atoms. 21.The polymer of claim 2, wherein L is a divalent, branched or unbranched,hydrocarbon chain, having from 3 to 15 carbon atoms.
 22. The polymer ofclaim 2, wherein L is a divalent, branched or inbranched, hydrocarbonchain, having from 6 to 10 carbon atoms.
 23. The polymer of claim 2,wherein L is a divalent hydrocarbon chain having 7, 8, or 9 carbonatoms.
 24. The polymer of claim 2, wherein L is a divalent hydrocarbonchain having 8 carbon atoms.
 25. The polymer of any one of claim 1,further comprising another therapeutic agent dispersed in the matrix ofthe polymer.
 26. The polymer of any one of claim 1, further comprisinganother therapeutic agent appended to the polymer backbone.
 27. Apharmaceutical composition comprising a polymer of claim 1 and apharmaceutically acceptable carrier.
 28. A therapeutic method fortreating a disease in an animal comprising administering to an animal inneed of such therapy, an effective amount of a polymer of claim
 1. 29. Atherapeutic method for producing an anaesthetic effect in an animalcomprising administering to an animal in need of such therapy, aneffective amount of a polymer of claim
 13. 30. A therapeutic method fortreating cancer comprising administering to an animal in need of suchtherapy, an effective amount of a polymer of claim
 10. 31. A therapeuticmethod for producing an anti-inflammatory effect in an animal comprisingadministering to an animal in need of such therapy, an effective amountof a polymer of claim
 8. 32. A method for producing a polymer asdescribed in claim 1 comprising co-polymerizing a compound, of formula(X₁—R¹—N═N—R¹—X₂) and a linker precursor of formula Z₁-L-₂, wherein eachR¹ is independently a group. that will provide a biologically activecompound upon hydrolysis of the polymer and cleavage of the azo-bond; Lis a liking group; and each of X₁, X₂, Z₁, and Z₂ is selected to providean anahydride linkage, an amide linkage, a thioester linkage, or anester linkage upon polymerization.
 33. A method of delivering abiologically active compound to a host comprising administering to thehost a biocompatible and biodegradable polyester or polyamnide ofclaim
 1. 34. The polymer as described in claim 1 for use in medicaltherapy.
 35. The use of a polymer as described in claim 1 for themanufacture of a medicament useful for the treatment of a disease in amammal, such as a human.